Abstract

A novel four stage Cascade of Moving Baffle Oscillatory Crystallisers (CMBOC) is developed, characterised and implemented for continuous crystallisation of pharmaceuticals. The platform was fully automated with pressure controlled slurry transfer and process analytical tools (PAT) to support process monitoring and control. Model predictive control was used to achieve precise temperature control during operation of crystallisations. Mixing and flow characterisation for liquids and slurries was performed confirming near-ideal mixing performance for mean residence times in the range 20–90 min. Heat transfer characteristics were determined and shown to be well suited to the demands of cooling crystallisation processes. Heat transfer efficiency increased with increasing oscillatory Reynolds number (Reo). This cascade is shown to provide the advantages of more uniform mixing and efficient heat transfer performance compared to a traditional cascade of stirred tank crystallisers. Continuous crystallisations of both alpha lactose monohydrate (ALM) and paracetamol (PCM) were carried out in which the target size, form, agglomeration and encrustation were controlled. For ALM, the products showed a narrow particle size distribution (PSD) with dv50 = 65 ± 5 μm and a span of 1.4 ± 0.2, and achieved a yield of 70%. The continuous crystallisation of paracetamol in the CMBOC produced non-agglomerated product with dv50 = 398 ± 20 μm with a span of 1.5 ± 0.2 and achieved an 85% yield. No fouling or encrustation in the vessels or transfer lines were observed during the processes. The flexible configuration and operation of the platform coupled with well characterised shear rate distribution, residence time distributions and heat transfer shows that this platform is well suited to a range of crystallisation modes including seeded, antisolvent, cooling or reactive processes, where careful control of crystal attributes is required.

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